DESCRIPTION (taken from the application) The goal of this project is to better understand the role played by the nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma in biology, using a variety of approaches both in vitro and in vivo. Already known to be a critical determinant of fat cell differentiation, PPAR gamma is found in several other cell types, including macrophages, type II pneumocytes of the lung, and the epithelium of breast, prostate, and colon. In the first part of this proposal, we will be assessing the requirement for PPAR gamma in the development of these and other lineages using chimeric mice derived from wild-type and PPAR gamma null embryonic stem cells. In the second part of the proposal, the requirement for PPAR gamma in adipogenesis will be probed further through the use of fibroblasts that lack the ability to express this receptor. Using these cells as a tool, specific processes in terminal differentiation can be tested, including the relative adipogenic potencies of PPAR gamma 1 and PPAR gamma 2, and the role of several natural and synthetic ligands. Some of these ligands are used clinically as insulin sensitizers in type 2 diabetes, which leads to the third aspect of this proposal. The role of PPAR-gamma in maintaining insulin sensitivity and insulin secretion in the beta cells of the pancreas will be tested using tissue-specific gene ablation technology in mice. Such animals, lacking PPAR gamma in the islet cells, are predicted to be unusually prone to both type 2 and, given certain clues in the literature, type 1 diabetes as well.